Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study, euglycemia could not be maintained even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring peptide produced and released from the gut in response to food. Of great interest is the finding that in type 2 diabetes, pharmacological doses of GLP-1 can normalize blood sugars, i.e. euglycemia is achieved. However, GLP-1 has a biological half-life of only 2-4 minutes and has to be given systemically. Its short half-life is partially due to rapid inactivation of the peptide by dipeptidyl peptidase IV (DPP IV) which cleaves off the first 2 amino acids. This means that it would have to be given continuously in order to maintain euglycemia. The Gila monster is a lizard whose natural habitat is in Arizona. It produces a peptide, called exendin-4, in its saliva which is a homolog of GLP-1. When it is given systematically to rodents, its biological half-life is 12-16 hours. We gave exendin-4 intraperitoneally, only once daily, to db/db mice and showed that the hemoglobin A1c, a marker of long-term control of blood glucose, was 5.7% in the treated animals vs. 9.1% in the non-treated animals and that it was about 10-fold more potent that GLP-1 (Diabetologia 42:45-50, 1999). We are expanding this project to find the effective concentration of exendin-4 that is anti-diabetogenic and we are looking at the mechanisms whereby exendin-4 has such beneficial long-term effects. We are also working on "humanizing" exendin-4 so that we can have a peptide as close as possible to GLP-1 but still retain the potency and biological half-life of exendin-4. This gives it a major advantage over GLP-1 and indeed over other peptides and if we find that exendin-4, in humans, can control blood glucose (see Exendin-4 is a Treatment for Type 2 Diabetes Z01AG00907) we will expand further on this finding. As regards rendering GLP-1 DPP IV resistant we have shown that placing a spacer between the first and second amino acids inhibits DPP IV function (Endocrinology 142:4462-4468, 2001). Currently, Amylin Corp. (San Diego) is involved in manufacturing a transdermal preparation of Exendin-4 which may only have to be replaced biweekly or monthly even. We have also been investigating the function of the nine amino acid addition that is at the C-terminal end of exendin-4.